Method for synthesis of halopyridyl-acyclopentane derivative and intermediate thereof

ABSTRACT

The present invention relates to a method for synthesis of an optically active halopyridyl-azacyclo-pentane derivative and the intermediate thereof which comprises preparing an optically active allene-1,3-dicarboxylic acid ester derivative from an optically active acetonedicarboxylic acid ester derivative and then proceeding through a 7-azabicyclo[2.2.1]heptane derivative to obtain the objective product.

TECHNICAL FIELD PERTINENT TO THE INVENTION

[0001] The present invention relates to a method for synthesis ofhalopyridyl-azacyclopentane derivative such as epibatidine, which is analkaloid having a strong analgesic activity as its pharmacologicaleffect, and the intermediate thereof. In more particular, the presentinvention relates to a novel method for synthesis ofhalopyridyl-azacyclopentane derivative and the intermediate thereof,which comprises preparing an optically active allene compound from anacetonedicarboxylic acid as a starting material, then preparing7-azabicyclo[2.2.1]heptane derivative as an intermediate throughDiels-Alder reaction of the optically active allene compound obtainedabove with pyrrole, so as to prepare halopyridyl-azacyclopentanederivative.

BACKGROUND ART

[0002] (−)-Epibatidine, which is an alkaloid isolated from the skin ofthe Ecuadorian poison frog, is attracting attention as an analgesicagent of utterly new type because it has as its pharmacological effect astrong analgesic activity of about 200 times more potent than that ofmorphine and moreover it has been suggested that its analgesic action isexhibited without the intermediation of opioid receptor. On the otherhand, though it has a strong toxicity, it possesses a very interestingphysiological activity; for example, it has recently been revealed thatit acts as an agonist for nicotinic acetylcholine receptors of thecentral nerve (Daly, J. W., et at., Mol. Pharm., 1994, 45, 563) and ithas been disclosed that its radiolabelled form is useful as an imagingagent for nicotinic acetylcholine receptors (U.S. Pat. No. 5,726,189).In addition to the interesting physiological activities described above,(−)-epibatidine has a unique mother skeleton,7-azabicyclo[2.2.1]heptane, so that a variety of methods forsynthesizing the compound have been studied.

[0003] For example, attempts have been made to synthesize anintermediate having the 7-azabicyclo-[2.2.1]heptane core and obtain (+)and (−)-epibatidine therefrom through the alkylation ofN-[(trifluoroacetyl)amino]cyclohex-3-ene (Fletcher, S. R. et al., J.Org. Chem., 1994, 59, 1771-1778), the Diels-Alder reaction ofp-toluylsulfonyl-acetylene with N-(t-butoxycarbonyl)pyrrole (Carrol, F.I. et al., J. Med. Chem., 1997, 40, 2293-2295), the Diels-Alder reactionof methyl 3-bromopropiolate with N-(t-butoxycarbonyl)pyrrole (Zhang, C.et al., J. Org. Chem., 1996, 61, 7189-7179) and method of synthesiswhich uses levulinic acid as the starting material (Rapoport, H. et al.,J. Org. Chem., 1995, 60, 2683-2691). These methods, however, have thedisadvantage of very low yield because the racemate obtained must besubjected to optical resolution to obtain the intended optically activeepibatidine. On the other hand, with regards to the asymmetric synthesisof epibatidine, there have been reported, for example, an asymmetricazidation which uses an asymmetric ligand and Pd (Trost, B. M. et al.,Tetrahedron Lett., 1996, 37, 7485-7488), an asymmetric protonation whichuses an asymmetric alcohol (Kosugi, H. F. et al., Chem. Commun., 1997,1857-1858), an asymmetric desulfonation which uses an asymmetric amine(Simpkins, N. S. et al., Tetrahedron Lett., 1998, 39, 1023-1024) and anasymmetric oxidation which uses microbial oxidation (Olivo, H. F. etal., Tetrahedron Lett., 1998, 39, 1309-1312). However, these methodshave disadvantages of requiring lengthy process steps or of a lowoptical purity of the product.

[0004] An allene compound is a useful substance which has the 1,2-dienestructure and, by virtue of its unique reactivity, can be used forsynthesis of various compounds in organic synthesis. A generally usedmethod for synthesizing an allene compound is the substitution reactionstarting from a propargyl compound which accompanies isomerization to anallene compound (Alexakis, A. et al., J. Am. Chem. Soc., 1990, 112,8042-8047). Other known methods include a substitution reaction using aGrignard's reagent which starts from a dithioacetal derivative (Luh, T.Y. et al., J. Org. Chem., 1996, 61, 8685) and synthesis of an allenecompound by Wittig reaction in which attention is directed to thespecies of ketene (Fuji, K. et al., Synlett, 1995, 933), but thesemethods cannot be applied to the synthesis of allene-1,3-dicarboxylicacid derivatives. Further, a method has been reported (Bryson, T. A. etal., Org. Synth., 1988, coll. VI, 505) which comprises chlorinatingdiethyl 1,3-acetone dicarboxylate with phosphorus pentachloride and thentreating the resulting product with triethylamine to obtain ethylallene-1,3-dicarboxylate. This method, however, has the disadvantage ofrequiring lengthy process steps and of a low yield of the product.

[0005] With regard to the example of using an allene compound forsynthesizing the bicyclo[2.2.1]heptane core, the synthesis of thebicyclo[2.2.1]heptane core through the Diels-Alder reaction of menthylallenecarboxylate with cyclopentadiene has been reported (Kanematsu, K.et al., J. Org. Chem., 1996, 61, 2031). A method of synthesis has beenrecently reported that the 7-azabicyclo[2.2.1]heptane core issynthesized through the Diels-Alder reaction of methyl allenecarboxylatewith a pyrrole derivative and the racemate of epibatidine is obtainedtherefrom (Trudell, M. L. et al., Tetrahedron Lett., 1997, 38,7993-7996). This method also has the disadvantage of requiring anoptical resolution step.

[0006] In view of the situations, the object of the present invention isto provide a method for synthesis of an optically activehalopyridyl-azacyclopentane derivative wherein an optically activeallene-1,3-dicarboxylic acid derivative and a7-azabicyclo[2.2.1]-heptane core derivative are employed as theintermediates and wherein the synthesis routes are shortened, theoperations are simple and a high optical yield can be obtained, and alsoa method for synthesis of the intermediates.

DISCLOSURE OF THE INVENTION

[0007] According to the present invention, there is provided a methodfor synthesis of a halopyridyl-azacyclopentane derivative whichcomprises the first step of allowing an optically activeacetonedicarboxylic acid ester derivative to react in the presence of abasic substance and a dehydrating agent to obtain a diastereomer mixtureof an allene-1,3-dicarboxylic acid ester derivative and then subjectingthe diastereomer mixture to asymmetric transformation to obtain anoptically active (R)- or (S)- allene-1,3-dicarboxylic acid esterderivative, the second step of subjecting the optically activeallene-1,3-dicarboxylic acid ester derivative to a Diels-Alder reactionwith a dienophile to obtain a 7-azabicyclo[2.2.1]heptene derivative andthen reducing the 7-azabicyclo[2.2.1]heptene derivative to obtain a7-azabicyclo[2.2.1]heptane derivative, and the third step of preparingan optically active halopyridyl-azacyclopentane derivative from the7-azabicyclo[2.2.1]-heptane derivative.

[0008] More specifically, there is provided a method for synthesis of ahalopyridyl-azacyclopentane derivative, wherein the optically activeacetone-dicarboxylic acid ester derivative is represented by the formula(1)

[0009] (wherein R¹ and R² are each a group derived from an opticallyactive alcohol and R³ and R⁴ are each a member selected from the groupconsisting of a hydrogen atom, alkyl group and aryl group, which may bethe same or different from each other),

[0010] the optically active allene-1,3-dicarboxylic acid esterderivative is R- or S-enantiomer represented by the formula (2)

[0011] (wherein R¹ and R² are each a group derived from an opticallyactive alcohol and R³ and R⁴ are each a member selected from the groupconsisting of a hydrogen atom, alkyl group and aryl group, which may bethe same or different from each other),

[0012] the optically active 7-azabicyclo[2.2.1]heptene derivative isrepresented by the formula (3), or the formula (4) which is itsenantiomer

[0013] (wherein R¹ and R² are each a group derived from an opticallyactive alcohol and R⁵ is a protective group for an amino group),

[0014] (wherein R¹ and R² are each a group derived from an opticallyactive alcohol and R⁵ is a protective group for an amino group),

[0015] the optically active 7-azabicyclo[2.2.1]heptane derivative is aketoester compound represented by the formula (5), or the formula (6)which is its enantiomer

[0016] (wherein R² is a group derived from an optically active alcoholand R⁵ is a protective group for an amino group),

[0017] (wherein R² is a group derived from an optically active alcoholand R⁵ is a protective group for an amino group), or is a ketonecompound represented by the formula (7)

[0018] (wherein R⁵ is a protective group for an amino group), and

[0019] the halopyridyl-azacyclopentane derivative is represented by theformula (8)

[0020] (wherein X is a halogen atom selected from Cl, F, Br and I or aradioactive isomer thereof).

[0021] The second aspect of the present invention relates to a methodfor synthesis of an optically active allene-1,3-dicarboxylic acid esterderivative, which is an intermediate for synthesis of thehalopyridyl-azabicyclo derivative. Thus, there is provided a method forsynthesis of an optically active allene-1,3-dicarboxylic acid esterderivative which comprises subjecting an acetonedicarboxylic acid and anoptically active alcohol to esterification in the presence of a basicsubstance and a dehydrating agent, or subjecting an acetonedicarboxylicacid ester (wherein the ester group is a lower alkyl or phenyl group)and an optically active alcohol to transesterification in the presenceof a basic substance, to obtain an optically active acetone-dicarboxylicacid ester derivative, then subjecting the optically activeacetonedicarboxylic acid ester derivative to alienation in the presenceof a basic substance and a dehydrating agent to obtain a mixture ofdiastereomers of an allene-1,3-dicarboxylic acid ester derivative, andthen subjecting the mixture of diasteromers to crystallization-inducedasymmetric transformation with cooling and crystallization in thepresence of a basic substance to obtain (R)-allene-1,3-dicarboxylic acidester derivative or (S)-allene-1,3-dicarboxylic acid ester derivative.

[0022] Another aspect of the present invention relates to a method forsynthesis of a ketoester compound or a ketone compound of an opticallyactive 7-azabicyclo-[2.2.1]heptane derivative useful as a precursor ofthe halopyridyl-azacyclo derivative represented by the formula (8).Thus, a ketoester compound of the optically active7-azabicyclo[2.2.1]heptane derivative represented by the formula (5) orits enantiomer of the formula (6) can be synthesized by subjecting theoptically active allene-1,3-dicarboxylic acid ester derivative obtainedby the above-mentioned method and a dienophile to Diels-Alder reactionto obtain the optically active 7-azabicyclo[2.2.1]heptene derivativerepresented by the formula (3) or its enantiomer of the formula (4),then selectively reducing the isolated olefin of the derivative, andsubjecting the resulting product to ozone decomposition,

[0023] (wherein X is a halogen atom selected from Cl, F, Br and I or aradioactive isomer thereof),

[0024] (wherein R¹ and R² are each a group derived from an opticallyactive alcohol and R⁵ is a protective group for an amino group),

[0025] (wherein R¹ and R² are each a group derived from an opticallyactive alcohol and R⁵ is a protective group for an amino group),

[0026] (wherein R² is a group derived from an optically active alcoholand R⁶ is a protective group for an amino group),

[0027] (wherein R² is a group derived from an optically active alcoholand R⁵ is a protective group for an amino group).

[0028] Further, the optically active 7-azabicyclo-[2.2.1]heptan-2-onerepresented by the formula (7) can be obtained by further subjecting theketoester derivative of the optically active7-azabicyclo[2.2.1]heptan-2-one represented by the formula (5) or theformula (6) to hydrolysis and decarbonation,

[0029] (wherein R⁵ is a protective group for an amino group).

[0030] In the above-mentioned aspects, the optically active alcohol ispreferably one selected from menthols, such as (−)-menthol, (+)-mentholand (+)-isomenthol, and binaphthol derivatives, such as(R)-(+)-1,1′-bi(2,2′-naphthol), (R)-(+)-1,1′-bi(2,2′-naphthol)monomethylester, (S)-(−)-1,1′-bi(2,2′-naphthol) and(S)-(−)-1,1′-bi(2,2′-naphthol)monomethyl ester; the dehydrating agent ispreferably one selected from 2-chloro-1,3-dimethyl-imidazolium chloride,2-chloro-1,3-dimethylimidazolinium hexafluorophosphate and the like, andthe basic substance is preferably one selected from tertiary amines,such as triethylamine and dimethylaminopyridine.

[0031] According to the present invention, from an acetonedicarboxylicacid or its lower alkyl ester as the starting material, an opticallyactive allene-1,3-dicarboxylic acid derivative having a high opticalpurity can be obtained, without conducting a complicated operation ofoptical resolution, through the synthesis of an optically activeacetonedicarboxylic acid ester, effective synthesis of a mixture ofdiastereomers of optically active allene-1,3-dicarboxylic acidderivative by alienation reaction, and asymmetric crystallization of themixture of diastereomers. By proceeding via the novel optically activeallene-1,3-dicarboxylic acid derivative synthesis, the7-azabicyclo[2.2.1]heptane derivative, which is the precursor of thehalopyridyl-azacyclopentane derivative, can be synthesized withshortened synthesis steps and with a high yield, and thus a novel methodfor total synthesis of an optically active halopyridyl-azacyclopentanederivative which includes the above-mentioned synthesis steps can beprovided.

BEST MODE FOR CARRYING OUT THE INVENTION

[0032] One mode of the synthesis route of the first step of the presentinvention is described below with reference to the formula (9), whereinR′ is a lower alkyl group or phenyl group, and R is a group derived froman optically active alcohol.

[0033] In the formula (9), an optically active 1,3-acetonedicarboxylicacid ester (II) is obtained by the esterification of acetonedicarboxylicacid (I)-a with an optically active alcohol or the transesterificationof an acetonedicarboxylic acid alkyl ester or phenyl ester (I)-b with anoptically active alcohol. When acetone-dicarboxylic acid (I)-a is used,for example (−)-menthol as the optically active alcohol and thecarboxylic acid (I)-a are added to the methylene chloride solution of2-chloro-1,3-dimethylimidazolinium chloride (hereinafter abbreviated asDMC), and pyridine is added dropwise thereto at room temperature toeffect esterification, whereby optically active menthyl1,3-acetonedicarboxylate (II) [R=(−)-menthyl group] is obtained.

[0034] At the stage of obtaining an optically active allene compound inthe above-mentioned process step, the acetone dicarboxylic acid dialkylester (I)-b (e.g., R′=methyl or ethyl) is preferably ref luxed togetherwith a basic substance, such as dimethylaminopyridine in a solvent suchas toluene, because thereby the trans-esterification proceeds easily and1,3-acetone-dicarboxylic acid menthyl ester (II) is obtained in aquantitative yield. This is a preferable mode of reaction because anacetonedicarboxylic acid dialkyl ester is easily obtainable, the yieldof transesterification is high and moreover the treatment after reactioncan be easily conducted.

[0035] Then the optically active 1,3-acetone-dicarboxylic acid menthylester (II) is added dropwise under ice cooling into methylene chloridecontaining DMC added thereto, subsequently triethylamine is addeddropwise thereto, and the resulting mixture is stirred at roomtemperature to effect alienation. Thus, the diastereomer mixture (III)of optically active allene-1,3-dimenthyl ester is obtained.

[0036] The diastereomer mixture is the mixture of(R)-allene-1,3-dimenthyl ester [(III)-R] and (S)-allene-1,3-dimenthylester [(III)-S], and the R- and S-enantiomers are in a rapid equilibriumrelation in the presence of triethylamine. Therefore, when thediastereomer mixture (III), in a pentane solution and in the presence ofa catalytic amount of triethylamine, is cooled to about −20˜−80° C. toeffect asymmetric transformation with simultaneous crystallization ofthe R-enantiomer (crystallization-induced asymmetric transformation,hereinafter referred to as asymmetric crystallization), the equilibriumis shifted, and the (R)-allene compound alone separates out. In theabove-mentioned example, (R)-allene-1,3-dimenthyl ester {(III)-R;[3R(1R,2S,5R)]-bis[5-methyl-2-(1-methylethyl)cyclohexyl]-2,3-pentadienedioate}alone can be obtained in a high yield. In the same manner, when(+)-menthol is used as the optically active alcohol,(S)-allene-1,3-dimenthyl ester [(III)-S] alone can be obtained.

[0037] According to the method of the first step of the presentinvention, the diastereomer mixture (III) of allene-1,3-dimenthyl estercan be obtained only by conducting two stages of reaction,esterification and dehydration (alienation). On the other hand,according to the previous methods, for example four stages of reactionare necessary, that is, methyl acetone-dicarboxylate is subjected tochlorination with phosphorus pentachloride, then demethylation withhydro-chloric acid, esterification with an optically active alcohol andthereafter dehydrochlorination. (Kanematsu K. et al., Tetrahedron Lett.,1992, 33, 5787-5790); thus, the preparation is complicated andtroublesome.

[0038] According to the present method, moreover, an about 1:1 mixtureof diastereomers is subjected, while being maintained in an equilibriumstate by means of the presence of a tertiary amine, to conditions underwhich one of the diastereomers alone will separate out, wherebyasymmetric crystallization is effected and a specific diastereomer canbe selectively obtained from a diastereomer mixture without resorting totroublesome optical resolution. Thus, the present method is a verysimple and highly efficient one.

[0039] In the present invention, the dehydrating agent used in theesterification of acetonedicarboxylic acid and the alienation of1,3-acetonedicarboxylic acid menthyl ester is preferably animidazolinium salt, such as 2-chloro-1,3-dimethylimidazolium chlorideand 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate. The basicsubstance used is preferably a tertiary amine having a high basicity,for example, trimethylamine, triethylamine, dimethylaminopyridine,N,N-diisopropyl-methylamine, N,N-diisopropylethylamine, pyrrolidine,(S)-2-methoxymethylpyrrolidine and sparteine.

[0040] It is as shown in Examples 1 and 2 that by using theabove-mentioned imidezolinium salt as the dehydrating agent and theamine as the basic substance, the reactions of esterification andalienation respectively proceed in one stage, and hence the presentmethod is useful for shortening the process steps and improving theyield. However, the allene-1,3-dicarboxylic acid esters obtained inExamples 1 and 2 are all racemate; thus, to obtain optically activecompounds, it is preferable to obtain an optically active allenecompound as the ester of an optically active alcohol andacetonedicarboxylic acid.

[0041] The optically active alcohols used for synthesizing theacetonedicarboxylic acid derivatives used in this step include, forexample, the following compounds:

[0042] (−)-menthol, (+)-menthol, (+)-isomenthol, (+)-borneol,(−)-borneol, (S)-(−)-2-methyl-1-butanol, (S)-(+)-4-decanol,(S)-(+)-3-tridecanol, (S)-(+)-3-undecanol, (S)-(+)-4-tetradecanol,(S)-(−)-2-methyl-1-decanol, (S)-(−)-2-methyl-1-dodecanol,(R)-2,2,2-trifluoro-1-(9-anthryl)ethanol,(S)-2,2,2-trifluoro-1-(9-anthryl)ethanol, (−)-8-phenylmenthol,(S)-(−)-1-phenyl-ethanol, (1R,2S)-(−)-2-phenyl-1-cyclohexanol,(1R,2S)-(+)-2-phenyl-1-cyclohexanol, (R)-(+)-1-phenylethanol,(S)-(+)-pentyloxy-2-propanol, (S)-(+)-1-octyloxy-2-propanol,(R)-(−)-2-octanol, (S)-(+)-2-octanol, (R)-(−)-2-nonanol,(S)-(+)-2-nonanol, (R)-(+)-endo-5-norbornen-2-ol,(R)-(+)-endo-5-norborneol, (S)-(−)-2-methyl-1-octanol, (S)-(−)-methyllactate, (R)-(+)-methyl lactate, (S)-(+)-methyl mandelate,(S)-(+)-methyl-3-hydroxy-2-methyl propionate,(R)-(−)-methyl-3-hydroxy-2-methyl propionate,(R)-(−)-methyl-2-hydroxypentanoate, (S)-(+)-methyl-3-hydroxypentanoate,methyl (R)-(−)-3-hydroxy-butyrate, methyl (S)-(+)-3-hydroxybutyrate,(R)-(−)-1,2-O-isopropylideneglycerol,(S)-(+)-1,2-O-isopropylidene-glycerol, (R)-4-hydroxypyrrolidone,(S)-4-hydroxy-pyrrolidone, (R)-2-hydroxy-1,2,2-triphenylethyl acetate,(S)-2-hydroxy-1,2,2-triphenylethyl acetate,(S)-2-hydroxy-2-phenylacetophenone,(R)-(−)-5-hydroxymethyl-2(5H)-furanone,(S)-(+)-hydroxymethyl-2(5H)-furanone,(R)-y-hydroxymethyl-y-butyrolactone,(S)-y-hydroxymethyl-y-butyrolactone, (S)-(+)-1-hexyloxy-2-propanol,(R)-(−)-2-heptanol, (S)-(+)-2-heptanol, (S)-(+)-1-heptyloxy-2-propanol,(R)-glycerol acetonide, (S)-glycerol acetonide,(R)-(+)-1-fluoro-2-octanol, (R)-1-fluoro-3-pentyloxy-2-propanol,(R)-1-fluoro-2-decanol, heptyloxy-2-propanol,(R)-1-fluoro-3-hexyloxy-2-propanol, (S)-(+)-2-ethyl-1-octanol,(R)-(−)-ethyl mandelate, (S)-(+)-ethyl mandelate,(R)-(+)-ethyl-4-chloro-3-hydroxybutanoate,(S)-(−)-ethyl-4-chloro-3-hydroxybutanoate,(R)-(−)-ethyl-3-hydroxybutanoate, (S)-(+)-2-dodecanol,(S)-(+)-4-dodecanol, (R)-diphenylprolinol, (S)-diphenylprolinol,(R)-di-2-naphthylprolinol, (S)-di-2-naphthylprolinol, (R)-(+)-dimethylmaleate, (S)-(−)-dimethyl maleate,(4S,5S)-(−)-4,5-dihydro-4-hydroxymethyl-2-methyl-5-phenyloxazole,(S)-(+)-6,6′-dibromo-1,1′-bi-2-naphthol,(S)-(+)-6,6′-dibromo-1,1′-bi-2-naphthol monomethyl ether,(R)-(−)-6,6′-dibromo-1,1′-bi-2-naphthol,(R)-(−)-6,6′-dibromo-1,1′-bi-2-naphthol monomethyl ether,(R)-(+)-4-chloro-3-hydroxybutyronitrile,(S)-(−)-4-chloro-3-hydroxybutyronitrile, (R)-(−)-3-chloromandelic acidester, (R)-(+)-1-chloro-2-decanol, (S)- (−)-2-chloro-1-decanol,(R)-(+)-chloro-2-dodecanol, (S)-(−)-2-chloro-1-dodecanol,(R)-(−)-1-chloro-3-hexyloxy-2-propanol, (S)-(−)-3-butyn-2-ol,(S)-(+)-t-butyl-3-hydroxy-butanoate, (R)-(+)-1,1′-bi(2,2′-naphthol),(R)-(+)-1,1′-bi(2,2′-naphthol)monomethyl ether,(S)-(−)-1,1′-bi(2,2′-naphthol) and(S)-(−)-1,1′-bi(2,2′-naphthol)monomethyl ether. Among the alcohols,those which have two functional groups, e.g., dialcohols andhydroxyacids, are preferably used after made into the form of monoalkylether or hydroxy acid ester by conventional methods to protect one ofthe functional groups.

[0043] The organic solvent used is not particularly restricted and maybe those conventionally used in organic synthesis. Preferably used arepentane, hexane, methylene chloride, tetrahydrofuran etc. Theesterification and the alienation are conducted at room temperature, andthe transesterification is conducted under reflux. The asymmetriccrystallization is carried out at a temperature range which is nothigher than room temperature and in which crystallization takes place,which may be properly selected according to the system concerned.

[0044] The second step of the present invention is the step of obtainingan optically active 7-azabicyclo-[2.2.1]heptane derivative by theDiels-Alder reaction of an optically active allene-1,3-dicarboxylic acidester with a dienophile. One mode of the second step is described belowwith reference to the following formula (10), wherein R is a groupderived from an optically active alcohol and Boc is the t-butoxycarbonylgroup.

[0045] The optically pure (R)-allene-1,3-dicarboxylic acid menthyl ester[(III)-R; R=(−)-menthyl group] obtained in the first step shown in theformula (9) is reacted with an N-acylpyrrole, e.g.,N-t-butoxycarbonyl-pyrrole, as a dienophile. The Diels-Alder reactionproceeds both in the presence and in the absence of a Lewis acid, butgives a higher selectivity when conducted in the presence of a Lewisacid. The amount of the Lewis acid added may be a catalytic amount andis not more than 1.5 equivalents, preferably not more than 1.2equivalents, relative to the allene compound. When a Lewis acid isabsent, the reaction is carried out with heating under reflux in asolvent. The amount of pyrrole used is not particularly limited, but ahigher yield can be obtained by using the excess thereof.

[0046] The dienophile favorably used is pyrrole, which is preferablyused as a compound wherein the amino group is protected with a loweraliphatic acyl group, aromatic acyl group, formyl group, vinyl group,lower alkoxy-carbonyl group, aralkylcarboxyl group, aryloxycarbonylgroup, aryloxycarbonyl group, aralkyl group, tri-lower alkylsilyl group,and the like. The lower aliphatic acyl group used is a group of 1-6carbon atoms, such as acetyl group, propionyl group, butyryl group,isobutyryl group, valeryl group, isovaleryl group and pivaloyl group.The aromatic acyl group may be, for example, the benzoyl group, toluoylgroup, xyloyl group and phenylacetyl group, the lower alkoxycarbonylgroup may be, for example, the methoxycarbonyl group, ethoxycarbonylgroup, propoxycarbonyl group, butoxycarbonyl group and t-butoxy-carbonylgroup, the aralkyloxycarbonyl group may be, for example, thebenzyloxycarbonyl group, methoxybenzyl-carbonyl group andchlorobenzyloxycarbonyl group, the aryloxycarbonyl group may be, forexample, the phenyloxycarbonyl group and nitrophenoxycarbonyl group, thearalkyl group may be, for example, the benzyl group, methoxybenzylgroup, nitrobenzyl group and chlorobenzyl group, and thetri-loweralkylsilyl group may be, for example, the trimethylsilyl group,triethylsilyl group and triphenylsilyl group.

[0047] The optically active 7-azabicyclo[2.2.1]heptene derivative (IV){[1S,2R(1R,2S,5R),3Z(1R,2S,5R),4R]-5-methyl-2-(1-methylethyl)cyclohexyl3-[2-[[5-methyl-2-(1-methylethyl)cyclohexyl]oxy]-2-oxoethylidene]-7-(t-butoxycarbonyl)-7-azabicyclo[2.2.1]hept-5-ene-2-carboxylate;R=(−)-menthylgroup} resulting from the Diels-Alder reaction is obtainedstereoselectively only in the form of endo-adduct.

[0048] The optically active 7-azabicyclo[2.2.1]heptene derivative (IV)has two kinds of olefin, of which the isolated olefin can be selectivelyreduced. The reduction may be conducted by using a conventionally usedreduction catalyst, such as Pt, Pd and Wilkinson complex, with hydrogenat about 10 atm. The reduction proceeds nearly quantitatively to give anoptically active 7-azabicyclo[2.2.1]heptane derivative (V).

[0049] The derivative (V) is then subjected to ozone decomposition toobtain an optically active 7-aza-bicyclo[2.2.1)heptan-2-one-3-carboxylicacid ester (VI), a ketoester compound. The ozone decomposition isconducted by using methylene chloride as the solvent and passing ozonegas through the reaction solution at about −70 to −80° C., and theozonide formed is decomposed with dimethyl sulfide ortriphenylphosphine. As compared with a case of using methanol as asolvent, wherein the ketoester compound is difficult to obtain directlyby ozone decomposition and it is necessary first to reduce the esterinto an alcohol and then to subject the alcohol to ozone decomposition,the present method can attain the intended object with a one stage lessreaction.

[0050] In the example described above the (−)-ketoester compound wasobtained by using a material wherein R is the (−)-menthyl group, whereaswhen (+)-menthol is used, the (+)-ketoester compound, namely(+)-7-azabicyclo[2.2.1]heptan-2-one-carboxylic acid ester (VI), can beobtained.

[0051] The third step of the present invention is the step ofsynthesizing a halopyridyl-azacyclopentane derivative, e.g.,(−)-epibatidine, by using as a precursor the optically active7-azabicyclo[2.2.1]heptan-2-one-3-carboxylic acid ester (VI) obtained inthe second step. One mode of this step is described below with referenceto the following formula (11) [R=(−)-menthyl group].

[0052] The 7-azabicyclo[2.2.1]heptan-2-one-carboxylic acid ester (VI)can be used for synthesis of epibatidine by using a known method(Fletcher et al., J. Org. Chem., 1994, 59, 1771-1778). Thus, the7-azabicyclo[2.2.1]-heptan-2-one-3-carboxylic acid ester (VI) issubjected to simultaneous hydrolysis and decarbonation with an acid toobtain 7-azabicyclo[2.2.1]heptan-2-one (VII), to which is then added2-chloro-5-iodopyridine in the presence of n-BuLi at −70° C., and theresulting addition product is then subjected to dehydration, reductionand deprotection of the amino group to obtain (−)-epibatidine (IX),which is one of the halopyridyl-azacyclopentane derivative and is anaturally obtainable optically active compound. This is alsodemonstrated from the fact that the angle of rotation [α]_(D) ¹⁷=−74.5and NMR data of(1R,4S)-7-(t-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one (VII)obtained in Example 13 are in good agreement with the angle of rotation[α]_(D) ¹⁷=−72.6 and NMR data reported for natural-type(1R,4S)-7-(t-butoxycarbonyl)-7-azabicyclo-[2.2.1]heptan-2-one (Rapoport,H. et al., J. Org. Chem., 1995, 60, 2683-2691).

[0053] The halopyridyl-azacyclopentane derivatives are represented bythe formula (8) as described above and include, for example,exo-2-(6′-chloro-3′-pyridyl)-7-azabicyclo[2.2.1]heptane,exo-2-(6′-bromo-3′-pyridyl)-7-azabicyclo[2.2.1]heptane,exo-2-(6′-fluoro-3′-pyridyl)-7-azabicyclo[2.2.1]heptane,exo-2-(6′-chloro-2′-pyridyl)-7-azabicyclo[2.2.1]heptane,exo-2-(6′-chloro-4′-pyridyl)-7-azabicyclo[2.2.1]heptane,exo-2-(5′-chloro-3′-pyridyl)-7-azabicyclo[2.2.1]heptane,exo-2-(4′-bromo-3′-pyridyl)-7-azabicyclo[2.2.1]heptane, andexo-2-(2′-chloro-3′-pyridyl)-7-azabicyclo[2.2.1]heptane. The halogenattached to the pyridyl group may be the radioactive isomer thereof.

EXAMPLES

[0054] The present invention is described in detail below with referenceto Examples, but the invention is in no way limited thereto.

[0055] The methods used for measuring the substances obtained and thesolvents commonly used are as follows.

[0056] (1) Melting point: YANAGIMOTO melting point measuring apparatuswas used.

[0057] (2) H¹-NMR: Determined with JEOL JMN-EX270, Varian XL-300spectrometer. The chemical shift value was indicated by ppm, withtetramethylsilane (TMS) used as the internal standard.

[0058] (3) Angle of rotation: Determined by using Horiba Sepa-200.

[0059] (4) Infrared spectra: Determined with Jasco IR-810, SHIMADZUFTIR-8300. The wave number was indicated by cm⁻¹.

[0060] (5) Mass spectra: Determined with JEOL JMX-SX102AQQ massspectrometer and JEOL JMS-Gcmate mass spectrometer.

[0061] (6) Elementary analysis: Determined with PERKINELMER SeriesCHNS/O Analyzer 2400.

[0062] (7) Column for column chromatography: Wakogel C-200 (Wako PureChemical Industries, Ltd.), Wakogel C-300 (Wako Pure ChemicalIndustries, Ltd.) and Kieselgel 60 Art. 9385 (Merck) were used.

[0063] (8) Preparative TLC column: Kieselgel 60 F₂₅₄ Art. 5715 (Merck)and Kieselgel 60 F₂₅₄ Art. 5744 (Merck) were used.

[0064] (9) Preparative HPLC: JAI LC-908 was used; columns used wereJAIGEL-1H and JAIGEL-2H.

[0065] (10) The ethereal solvents and the aromatic solvents employed forreaction were distilled from sodium-benzophenone ketyl before use.Methylene chloride used was washed 10 times with water to removemethanol, the stabilizer, and distilled from CaH₂ before use. Otheranhydrous solvents used were made anhydrous by conventional methods. TheNaH employed for reaction was used after freed from oily substances bywashing 3 times with ether.

Example 1

[0066] Synthesis of Allene-1,3-dicarboxylate Using DMC

[0067] Under nitrogen gas stream, 100 ml of dry methylene chloride wasadded to 5.80 g (34.5 mmol) of a dehydrating agent DMC, and 5.00 g (28.7mmol) of dimethyl-1,3-acetonedicarboxylate was added dropwise to theresulting DMC solution with ice cooling, then 11.6 g (115 mmol, 4equivalents relative to dimethyl-1,3-acetonedicarboxylate) oftriethylamine (Et₃N) was added dropwise thereto, and the resultingmixture was stirred at room temperature for one hour. After completionof the reaction, the reaction mixture was purified by columnchromatography on silica gel, whereby 4.05 g ofdimethyl-1,3-acetonedicarboxylate was obtained. Yield 90%.

[0068] Yellow oil; H¹-NMR(CDCl₃, 270 MHz) δ: 6.06 (s, 2H), 3.78 (s, 6H);IR (CHCl₃): 3036, 2955, 2359, 1967, 1720, 1439, 1269 cm⁻¹; EI-MS m/z 156(M⁺, 7), 128 (100), 112 (23), 98 (3); HRMS 156.0422: C₇H₈O₄(M⁺) 156.0420

[0069] Reactions were carried out in the same manner as above wherein,while the amount of DMC used was fixed at 1.2 equivalents, the amount ofEt₃N used was varied in the range from 1 to 3 equivalents relative todimethyl-1,3-acetonedicarboxylate and the ester group was changed to themethyl group, ethyl group, benzyl group and t-butyl group. The resultsobtained are shown in Table 1. The yields were shown for the compounds(A) and (B) of the following formula (12).

[0070] It can be seen that when the amount of Et₃N used is less than 3equivalents relative to the 1,3-acetonedicarboxylic acid ester, vinylchloride (B) is formed as a by-product, whereas when it is 3 equivalentsor more, allene compounds alone can be obtained in a yield not lowerthan 70%. TABLE 1 Et₃N Time Yield Yield No. R R¹ equivalent (Hr) (A) (%)(B) (%) 1 Me H 1 24 — 44 2 Me H 2 22 72 21 3 Me H 3 1 90 — 4 Me Me 3 273 — 5 Et H 3 0.5 92 — 6 Bn H 3 2.5 70 — 7 t-Bu H 3 0.5 71 — (12)

Example 2

[0071] Synthesis of Allene-1,3-dicarboxylate Using Various Bases

[0072] In the reaction of transforming acetone-dicarboxylic acid estersinto allene-1,3-dicarboxylates shown in the formula (12), the behaviorof the reaction was studied by using various amines in place oftriethylamine. By using dimethyl 1,3-acetone-dicarboxylate as thereaction substrate and using 1.2 equivalents of DMC and 3 equivalents ofvarious amines, allene compounds were synthesized in methylene chlorideat room temperature. The results obtained are shown in Table 2 below.

[0073] When pyridine, which is weaker in basicity than triethylamine,was used, the reaction did not proceed but with other amines listed thepresent reactions all proceeded to give allene compounds (A). Even whenan optically active amine, (S)-2-methoxymethylpyrrolidine or sparteine,was used, racemate was formed and an optically active allene compoundcould not be obtained. TABLE 2 Time Yield Yield No. Base (Hr) (%) (A)(%) (B) 1 Triethylamine 1 90 — 2 N,N-Diisopropylethyl- 1.5 84  8 amine 3Pyridine 15 n.r. n.r. 4 (S)-2-Methoxymethyl- 0.5 61 23 pyrrolidine 5Sparteine 1 78 —

Example 3

[0074] Synthesis of1R,2S,5R-bis[5-methyl-2-(1-methylethyl)cyclohexyl]-1,3-acetonedicarboxylate

[0075] By using (−)-menthol, optically active acetonedicarboxylic acidmenthyl ester was synthesized. Under nitrogen gas stream, 5.00 g (34.2mmol) of acetonedicarboxylic acid and 10.7 g (68.4 mmol) of (−)-mentholwere added to a solution of 12.7 g (75.3 mmol) of DMC in 50 ml drymethylene chloride, then 10.8 g (137 mmol) of pyridine was addeddropwise thereto in a water bath and the resulting mixture was stirredat room temperature for 7.5 hours. After completion of the reaction, thedeposited solid was filtered with celite, and the crude product obtainedwas purified by silica gel column chromatography (AcOEt: hexane=1:20) toobtain 6.48 g of1R,2S,5R-bis[5-methyl-2-(1-methylethyl)-cyclohexyl]-1,3-acetonedicarboxylate.Yield 45%.

[0076] Pale yellow oil; H¹-NMR(CDCl₃, 300 MHz) δ: 4.80-4.68 (m, 2H),3.58 (d, J=5.9 Hz, 4H), 2.05-1.99 (m, 2H), 1.89-1.84 (m, 2H), 1.70-1.65(m, 4H), 1.59-0.75 (m, 28H); IR (CHCl₃): 2961, 2930, 1724, 1653, 1456,1244, 1180 cm⁻¹; FAB-MS m/z 423 [M+H]⁺; HRMS 423.3110: C₂₅H₄₃O₅ [M+H]⁺423.3119

Example 4

[0077] Synthesis of Diastereomer Mixture of[3R(1R,2S,5R)]-bis[5-methyl-2-(1-methylethyl)cyclohexyl]-2,3-pentadienedioateand[3S(1R,2S,5R)]-bis[5-methyl-2(1-methylethyl)cyclohexyl]-2,3-pentadienedioate

[0078] Under nitrogen gas stream, 100 ml of dry methylene chloride wasadded to 5.80 g (34.5 mmol) of a dehydrating agent DMC, and 100 mg(0.350 mmol) of the1R,2S,5R-bis[5-methyl-2-(1-methylethyl)cyclohexyl]-1,3-acetonedicarboxylatesynthesized in Example 3 was added dropwise with ice cooling to theresulting MDC solution, then 11.6 g (115 mmol) of Et₃N was addeddropwise thereto, and the resulting mixture was stirred at roomtemperature for 0.5 hour, to obtain 82.7 mg of a diastereomer mixture ofoptically active allenedicarboxylic acid dimenthyl ester in 86% yield.

[0079] Yellow oil; H¹-NMR (CDCl_(3, 270) MHz) δ: 6.01 (s, 1.1H), 5.99(s, 0.9H), 4.75 (dt, J=10.8, 4.4 Hz, 2H), 2.03 (br.d, J=11.9 Hz, 2H),1.87, 1.84 (qd, J=6.9, 2.6 Hz, total 6H), 1.77-1.63 (m, 4H), 1.63-1.34(m, 6H), 1.18-0.91 (m, 16H), 0.78, 0.77 (d, J=6.9 Hz, total 6H); IR(CHCl₃): 1945, 1685 cm⁻¹; FAB-MS m/z 405 [M+H]⁺; HRMS 405.3005:C₂₅H₄₁O₄[M+H]⁺ 405.3013

Example 5

[0080] Asymmetrization Reaction of Diastereomer Mixture; Synthesis of[3R(1R,2S,5R)]-bis[5-methyl-2-(1-methylethyl)cyclohexyl]-2,3-pentadienedioate

[0081] Crystallization-induced asymmetric transformation (asymmetriccrystallization) of a diastereomer mixture was conducted.

[0082] To 5 ml of a pentane solution of 2 g (4.95 mmol) of thediastereomer mixture (R:S=4:5) obtained in Example 4 was added 5.00 mg(0.05 mmol) of Et₃N, and the resulting mixture was placed in arefrigeration chamber and allowed to stand for one day while being keptat −20° C. After large grains of crystals had been deposited, themixture was further allowed to stand for one day at −78° C. After smallgrains of crystals had been deposited, the mother liquor was removedwith a pipette at −78° C., care being taken so that the crystals mightnot be sucked up. The crystals were washed 4-5 times with a small amountof cooled pentane, and the solvent remaining in crystals was evaporatedin vacuo. The mother liquor removed above was further subjected to thesame operation repeatedly two times. Thus, 1.8 g of crystals wasobtained. The crystals obtained were only of the R-enantiomer. Yield was90%.

[0083] Colorless crystal; mp: 83° C.; [α]_(D) ¹⁷: −240.1 (c=1.1, CHCl₃);H¹-NMR (CDCl₃, 300 MHz) δ: 5.99 (s, 2H), 4.75 (dt, J=10.8, 4.4 Hz, 2H),2.03 (br.d, J=11.9 Hz, 2H), 1.87, 1.84 (qd, J=6.9, 2.6 Hz, total 6H),1.77-1.63 (m, 4H), 1.63-1.34 (m, 6H), 1.18-0.91 (m, 16H), 0.78, 0.77 (d,J=6.9 Hz, total 6H); IR (CHCl₃): 1945, 1685 cm⁻¹; FAB-MS m/z 405[M+H]⁺;HRMS 405.3005: C₂₅H₄₁O₄[M+H]⁺ 405.3013

Example 6

[0084] Diels-Alder Reaction of Allene-1,3-dicarboxylic Acid Derivativewith Pyrrole Derivative

[0085] By using allene-1,3-dicarboxylic acid methyl ester as the allenecompound, the Diels-Alder reaction thereof with a pyrrole derivative wasconducted under various conditions.

[0086] Method 1:

[0087] Under nitrogen gas stream, 224 mg (1.68 mmol) of AlCl₃ was addedto 25 ml of a dry methylene chloride solution of 620 mg (1.53 mmol) ofallene-1,3-dicarboxylic acid methyl ester at −78° C., the resultingmixture was stirred for 30 minutes, then N-butoxycarbonylpyrrole wasadded dropwise thereto and the mixture was stirred at −78° C. for 13hours. After completion of the reaction, the reaction liquid was pouredinto water, then extracted with chloroform, the extract was dried withNa₂SO₄, filtrated and the solvent was evaporated in vacuo. The crudeproduct thus obtained was purified by silica gel chromatography(AcOEt:hexane=1:4) to obtain 681 mg of methyl3-(2-methoxy-2-oxoethylidene)-7-(t-butoxycarbonyl)-7-azabicyclo[2.2.1]hept-5-ene-2-carboxylate.Yield 73%.

[0088] Method 2:

[0089] Under nitrogen gas stream, 1.10 g (6.40 mmol) ofN-butoxycarbonylpyrrole was added dropwise to a solution of 100 mg (0.64mmol) of allene-1,3-dicarboxylic acid methyl ester in 10 ml of a drymethylene chloride, and the resulting mixture was stirred for 24 hourswith heating at 90° C. After completion of the reaction, the solvent wasevaporated in vacuo, and the resulting crude product was purified bysilica gel chromatography to obtain 184 mg of methyl3-(2-methoxy-2-oxoethylidene)-7-(t-butoxycarbonyl)-7-azabicyclo[2.2.1]hept-5-ene-2-carboxylate.Yield 89%.

[0090] Yellow oil; H¹-NMR(CDCl₃, 300 MHz) δ: 6.24-6.30 (m, 2H), 6.07 (d,J=1.7 Hz, 1H), 5.1-4.98 (m, 2H), 3.99 (s, 1H), 3.68 (s, 3H), 3.67 (s,3H), 1.41 (s, 9H); IR (CHCl₃): 3032, 3013, 2934, 1711, 1369, 1231, 1167cm⁻¹; FAB-MS m/z 324[M+H]⁺; HRMS 324.1447: C₁₆H₂₂O₆N[M+H]⁺ 324.1459

[0091] The results of experiments made under varied conditions are shownin Table 3 below.

[0092] Experiment Nos. 1-4 were conducted by the method 1, and theamount of Lewis acid used was 1.2 equivalents in each of theexperiments. Experiment Nos. 5-7 were conducted by the method 2 whereinheating at 90° C. under reflux in toluene was adopted. Through all ofthe experiments, the use of pyrrole in excess improves the yield,whereas the use of a Lewis acid gives a better selectivity. TABLE 3Dienophile Temp. Yield No. equivalent Lewis Solvent (° C.) (%) 1 2 AlCl₃CH₂Cl₂ −78→0 30 2 2 AlCl₃ CH₂Cl₂ −78 41 3 2 Sc(CF₃SO₃)₃ CH₂Cl₂ −78 47 410 AlCl₃ CH₂Cl₂ −78 73 5 1 — Toluene   90 43 6 2 — Toluene   90 68 7 10— Toluene   90 89

Example 7

[0093] Synthesis of [1S,2R(1R,2S,5R),3Z-(1R,2S,5R),4R]-5-methyl-2-(1-methylethyl)cyclohexyl3-[2-[[5-methyl-2-(1-methylethyl)cyclohexyl]oxy]-2-oxoethylidene]-7-(t-butoxycarbonyl)-7-azabicyclo[2.2.1]-hept-5-ene-2-carboxylate

[0094] By using 880 mg (2.20 mmol) of the optically active(R)-allenecarboxylic acid menthyl ester synthesized in Example 5,according to a similar procedure to that in the synthesis example bymeans of a Diels-Alder reaction using AlCl₃ shown in Example 6 (method1), with 9 hours of stirring, 1.08 g of an optically active compound(IV) shown in the formula (10), [1S,2R(1R,2S,5R),3Z(1R,2S,5R),4R]-5-methyl-2-(1-methylethyl)cyclohexyl3-[2-[[5-methyl-2-(1-metnylethyl)-cyclohexyl]oxy]-2-oxoethylidene]-7-(t-butoxycarbonyl)-7-azabicyclo[2.2.1]hept-5-ene-2-carboxylate(R=(−)-menthyl group), was obtained. Yield 86%.

[0095] Colorless crystal; mp: 140-142.7° C.; [α]_(D) ¹⁷: −3.2 (c=0.68,CHCl₃); H¹-NMR (CDCl₃, 300 MHz) δ: 6.42-6.30 (m, 2H), 6.04 (d, J=1.7 Hz,1H), 5.02-4.80 (m, 2H), 4.61 (ddd, J=10.8, 10.8, 4.3 Hz, 1H), 4.55 (dt,J=10.8, 4.4 Hz, 1H), 4.06 (s, 1H), 2.05-1.84 (m, 4H), 1.41 (s, 9H),1.68-0.69 (m, 34H); IR(CHCl₃): 2958, 2930, 1705, 1369, 1175 cm⁻¹; FAB-MSm/z 572(M+H]⁺; HRMS 572.3951: C₁₄H₅₄O₆N[M+H]⁺ 572.3955

Example 8

[0096] Reduction of Isolated Olefin; Synthesis ofExo-methyl-2-(2-methoxy-2-oxoethylidene)-7-(t-butoxy-carbonyl)-7-azabicyclo[2.2.1]heptane-3-carboxylateandendo-methyl-2-(2-methoxy-2-oxoethylidene)-7-(t-butoxy-carbonyl)-7-azabicyclo[2.2.1]heptane-3-carboxylate

[0097] To a solution of 4.90 g (15.2 mmol) of the compound synthesizedin Example 6,methyl-2-(2-methoxy-2-oxoethylidene)-7-(t-butoxycarbonyl)-7-azabicyclo[2.2.1]hept-5-ene-3-carboxylatein 15 ml methanol, was added 140 mg (0.15 mmol) of Wilkinson complex,[(C₆H₅)₃P]₃RhCl, and the resulting mixture was stirred under an inertatmosphere of hydrogen at 10 atm. for 15 hours. After completion of thereaction, metallic Rh was removed by celite filtration, the filtrate wasconcentrated in vacuo, and the resulting crude product was purified bysilica gel chromatography (AcOEt:hexane=1:5) to obtain 2.69 g (55%yield) of the exo-adduct and 2.24 g (45% yield) of the endo-adduct.

[0098] exo-adduct: pale yellow oil; H¹-NMR(CDCl₃, 300 MHz) δ: 6.00 (s,1H), 4.82-4.49 (m, 2H), 3.69 (s, 1H), 3.67 (s, 6H), 2.05-1.95 (m, 2H),1.60-1.45 (m, 2H), 1.43 (s, 9H); IR (CHCl₃): 3030, 3013, 2983, 1734,1699, 1367, 1229, 1163 cm⁻¹; FAB-MS m/z 326[M+H]⁺; HRMS 326.1604:C₁₆H₂₄O₆N[M+H]⁺ 326.1618

[0099] endo-adduct: pale yellow oil; H¹-NMR (CDCl₃, 300 MHZ) δ: 5.92 (d,J=2.5 Hz, 1H), 4.59 (d, J=4.9 Hz, 1H), 4.53 (t, J=4.4 Hz, 1H), 1.81-1.58(m, 3H), 1.43 (s, 9H); IR (CHCl₃): 3030, 3013, 2953, 1701, 1367, 1231,1163 cm⁻¹; FAB-MS m/z 326[M+H]⁺; HRMS 326.1604: C₁₆H₂₄O₆N[M+H]⁺ 326.1618

Example 9

[0100] Synthesis of[1S,2R(1R,2S,5R),3Z-(1R,2S,5R),4R]-5-methyl-2-(1-methylethyl)cyclohexyl3-[2-[[5-methyl-2-(1-methylethyl)cyclohexyl]oxy]-2-oxoethylidene]-7-(t-butoxycarbonyl)-7-azabicyclo[2.2.1]-heptane-2-carboxylate

[0101] To a solution of 578 mg (1.01 mmol) of the optically activecompound obtained in Example 7,[1S,2R(1R,2S,5R),3Z(1R,2S,5R),4R]-5-methyl-2-(1-methylethyl)cyclohexyl3-[2-[[5-methyl-2-(1-methylethyl)cyclohexyl]oxy]-2-oxoethylidene]-7-(t-butoxycarbonyl)-7-azabicyclo[2.2.1]hept-5-ene-2-carboxylatein 15 ml ethyl acetate, was added 10 mg of 10% Pd-C, and the resultingmixture was stirred under an inert atmosphere of hydrogen at 10 atm. for5 hours. After completion of the reaction, metallic Pd was removed bycelite filtration, the filtrate was concentrated in vacuo, and theresulting crude product was purified by PTLC (AcOEt:hexane=1:10) toobtain 573 mg of the objective product. Yield 99%.

[0102] White powder; mp: 152.0-152.6° C.; [α]_(D) ¹⁷: −75.1 (c=1.2,CHCl₃); H¹-NMR (CDCl₃), 300 MHz) δ: 5.88 (d, J=2.6 Hz, 1H), 4.63 (tt,J=10.6, 4.2 Hz, 2H), 4.54-4.50 (m, 2H), 4.00-3.99 (m, 1H), 2.15-1.49 (m,10H), 1.43 (s, 9H), 1.41-0.87 (m, 24H), 0.77, 0.72 (d, J=6.9 Hz, total6H); IR (CHCl₃): 2959, 2872, 1701, 1369, 1161 cm⁻¹; FAB-MS m/z572[M+H]⁺; HRMS 574.4106: C₃₄H₅₆O₆N[M+H]⁺ 574.4135

Example 10

[0103] Synthesis of7-(t-butoxycarbonyl)-3-methoxycarbonyl-7-azabicyclo[2.2.1]heptan-2-one

[0104] Ozone gas was bubbled through a solution of 90 mg (0.28 mmol) ofthe endo-adduct obtained in Example 8,endo-methyl-2-(2-methoxy-2-oxoethylidene)-7-(t-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane-3-carboxylate,in 15 ml methylene chloride, at −78° C. After confirming that thereaction solution had turned blue, ozone gas was bubbled for 1.5 hours.Then oxygen and nitrogen were bubbled through the solution to removeexcess ozone gas, thereafter 86 mg (1.38 mmol) of Me₂S was addeddropwise thereto, and the resulting mixture was stirred at roomtemperature for 14 hours. After completion of the reaction, the solventwas removed and the resulting crude product was purified by silica gelchromatography (AcOEt:hexane=1:2) to obtain 56.0 mg of the objectiveproduct as a diastereomer mixture of oxo-adduct:endo-adduct=1:1. Yield74%.

[0105] Colorless oil; H¹-NMR(CDCl₃, 300 MHz) δ: 4.85 (d, J=4.9 Hz,0.5H), 4.74 (dd, J=5.1, 4.1 Hz, 0.5H), 4.37 (d, J=4.3 Hz, 0.5H), 4.33(d, J=5.1 Hz, 0.5H), 3.76 (s, 3×0.5H), 3.74 (s, 3×0.5H), 3.46 (d, J=5.1Hz, 0.5H), 3.01 (s, 0.5H), 2.09-2.00 (m, 2H), 1.73-1.64 (m, 2H), 1.64(s, 9H); IR (CHCl₃): 2984, 2959, 1778, 1734, 1701, 1369, 1159, 1103cm⁻¹; FAB-MS m/z 270[M+H]⁺;HRMS 270.1342: C₁₃H₂₀O₅N[M+H]⁺ 270.1349

Example 11

[0106] Synthesis of[1S,2R(1R,2S,5R),3Z-(1R,2S,5R),4R]-5-methyl-2-(1-methylethyl)cyclohexyl7-(t-butoxycarbonyl]-3-oxo-7-azabicyclo[2.2.1]heptane-2-carboxylate

[0107] Ozone gas was bubbled through a solution of 100 mg (0.170 mmol)of the optically active compound obtained in Example 9,[1S,2R(1R,2S,5R),3Z(1R,2S,5R),4R]-5-methyl-2-(1-methylethyl)cyclohexyl3-[2-[[5-methyl-2-(1-methylethyl)cyclohexyl]oxy]-2-oxoethylidene]-7-(t-butoxy-carbonyl)-7-azabicyclo[2.2.1]heptane-2-carboxylate,in 20 ml methylene chloride, at −78° C. After confirming that thereaction solution had turned blue, ozone gas was bubbled for 30 minutes.Then O₂ and N₂ were bubbled through the solution to remove excess ozone,thereafter 137 mg (0.520 mmol) of Ph₃P was added thereto, and theresulting mixture was stirred at room temperature for 12 hours. Aftercompletion of the reaction the solvent was evaporated in vacuo, and theresulting crude product was purified by silica gel chromatography(AcOEt:hexane=1:5) to obtain the intended substance as a diastereomermixture of oxo-adduct:endo-adduct=1:1.

[0108] Pale yellow oil; [α]_(D) ¹⁶: −70.9 (c=0.92, CHCl₃); H¹-NMR(CDCl₃, 300 MHz) δ: 4.85-4.84 (m, 0.5H), 4.77-4.68 (m, 2×0.5H),4.38-4.37 (m, 0.5H), 4.31 (d, J=5.6 Hz, 0.5H), 3.43 (d, J=5.2 Hz, 0.5H),2.97 (s, 0.5H), 2.05-1.88 (m, 6H), 1.73-1.63 (m, 5H), 1.52-1.43 (m,1.5H), 1.46 (s, 9H), 1.26-0.88 (m, 7H), 0.75 (d, J=6.8 Hz, 3H); IR(CHCl₃): 2959, 1778, 1717, 1701, 1369, 1221, 1161 cm⁻¹; FAB-MS m/z394[M+H]⁺; HRMS 394.2594: C₂₂H₃₆O₅N[M+H]⁺ 394.2607

Example 12

[0109] Synthesis of 7-(t-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one

[0110] To 180 mg (0.970 mmol) of the diastereomer mixture obtained inExample 10,7-(t-butoxycarbonyl)-3-methoxycarbonyl-7-azabicyclo[2.2.1]heptan-2-one,was added 3 ml of 10% HCl and the resulting mixture was heated underreflux at 100° C. for 3.5 hours. After completion of the reaction thesolvent was evaporated in vacuo and the remaining water was removed byazeotropic distillation with ethanol. The crude product obtained wasdissolved with 10 ml of dry methylene chloride, 169 ml (1.68 mmol) ofEt₃N and 292 mg (1.34 mmol) of (Boc)₂O were added to the solution andthe resulting mixture was stirred at room temperature for 12 hours.After completion of the reaction, the reaction mixture was poured into asaturated aqueous sodium chloride solution, then extracted withchloroform, the extract was dried with Na₂SO₄, then filtrated and thesolvent was evaporated in vacuo. The crude product thus obtained waspurified by silica gel chromatography (AcOEt:hexane=1:3) to obtain 91.0mg of 7-(t-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one. Yield 64%.

[0111] Colorless oil (solidifies on standing); mp: 60-62° C.; H¹-NMR(CDCl₃, 300 MHz) δ: 4.55 (t, J=4.5 Hz, 1H), 4.24 (d, J=4.9 Hz, 1H),2.50-2.43 (m, 1H), 2.09-1.51 (m, 5H), 1.53 (s, 9H); IR (CHCl₃): 1760,1690 cm⁻¹; FAB-MS m/z 212[M+H]⁺; HRMS 212.1287: C₁₁H₁₅O₃N[M+H]⁺ 212.1297

Example 13

[0112] Synthesis of(1R,4S)-7-(t-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one

[0113] To 100 mg (0.250 mmol) of the optically active compound obtainedin Example 11,[1S,2R(1R,2S,5R),3Z-(1R,2S,5R),4R]-5-methyl-2-(1-methylethyl)cyclohexyl7-(t-butoxycarbonyl)-3-oxo-7-azabicyclo[2.2.1]heptane-2-carboxylate wasadded 3 ml of an aqueous 10% HCl solution and the resulting mixture wasstirred with heating at 100° C. under reflux for 3.5 hours. Aftercompletion of the reaction, the solvent was removed and the remainingwater was removed by azeotropic distillation with ethanol. The crudeproduct thus obtained was dissolved with 10 ml of dry methylenechloride, 77 ml (0.760 ml) of Et₃N and 111 mg (0.51 mmol) of (Boc)₂Owere added to the solution, and the resulting mixture was stirred atroom temperature for 12 hours. After completion of the reaction, thereaction mixture was poured into a saturated sodium chloride solution,then extracted with chloroform, the extract was dried with Na₂SO₄,filtered and the solvent was evaporated in vacuo. The crude product thusobtained was purified by silica gel chromatography (AcOEt:hexane=1:4) toobtain 29 mg of the objective substance. Yield 55%.

[0114] Colorless oil (solidifies on standing); mp: 60-62° C.; [α]_(D)¹⁷: −74.5 (c=1.0, CHCl₃); H¹-NMR (CDCl₃, 300 MHz) δ: 4.55 (t, J=4.5 Hz,1H), 4.24 (d, J=4.9 Hz, 1H), 2.50-2.43 (m, 1H), 2.09-1.51 (m, 5H), 1.53(s, 9H); IR (CHCl₃): 1760, 1690 cm⁻¹; FAB-MS m/z 212[M+H]⁺; HRMS212.1287: C₁₁H₁₈O₃N[M+H]⁺ 212.1297

1. A method for synthesis of a halopyridyl-azacyclopentane derivativewhich comprises the first step of allowing an acetonedicarboxylic acidester derivative of an optically active alcohol to react in the presenceof a basic substance and a dehydrating agent to obtain a diastereomermixture of an allene-1,3-dicarboxylic acid ester derivative and thensubjecting the diastereomer mixture to asymmetric transformation toobtain an optically active (R)- or (S)-allene-1,3-dicarboxylic acidester derivative, the second step of subjecting the optically activeallene-1,3-dicarboxylic acid ester derivative to a Diels-Alder reactionwith a dienophile to obtain a 7-azabicyclo[2.2.1]heptene derivative andthen reducing the 7-azabicyclo[2.2.1]heptene derivative to obtain a7-azabicyclo[2.2.1]heptane derivative and the third step of preparing anoptically active halopyridyl-azacyclopentane derivative from the7-azabicyclo[2.2.1]-heptane derivative.
 2. The method for synthesis of ahalopyridyl-azacyclopentane derivative according to claim 1, wherein theacetonedicarboxylic acid ester derivative of an optically active alcoholis represented by the formula (1)

(wherein R¹ and R² are each a group derived from an optically activealcohol and R³ and R⁴ are each a member selected from the groupconsisting of a hydrogen atom, alkyl group and aryl group, which may bethe same or different from each other), the optically activeallene-1,3-dicarboxylic acid ester derivative is R- or S-enantiomerrepresented by the formula (2)

(wherein R¹ and R² are each a group derived from an optically activealcohol and R³ and R⁴ are each a member selected from the groupconsisting of a hydrogen atom, alkyl group and aryl group, which may bethe same or different from each other), the optically active7-azabicyclo[2.2.1]heptene derivative is represented by the formula (3),or the formula (4), which is its enantiomer

(wherein R¹ and R² are each a group derived from an optically activealcohol and R⁵ is a protective group for an amino group),

(wherein R¹ and R² are each a group derived from an optically activealcohol and R⁵ is a protective group for an amino group), the opticallyactive 7-azabicyclo[2.2.1]heptane derivative is a ketoester compoundrepresented by the formula (5), or the formula (6), which is itsenantiomer

(wherein R² is a group derived from an optically active alcohol and R⁵is a protective group for an amino group),

(wherein R² is a group derived from an optically active alcohol and R⁵is a protective group for an amino group), or is a ketone compoundrepresented by the formula (7)

(wherein R⁵ is a protective group for an amino group), and thehalopyridyl-azacyclopentane derivative is represented by the formula (8)

(wherein X is a halogen atom selected from Cl, F, Br and I or aradioactive isomer thereof).
 3. The method for synthesis of ahalopyridyl-azacyclopentane derivative according to claim 1 or 2,wherein the optically active alcohol is a member selected from the groupconsisting of menthol, its derivatives, binaphthol and its derivatives.4. The method for synthesis of a halopyridyl-azacyclopentane derivativeaccording to any one of the claims 1-3, wherein the dehydrating agent is2-chloro-1,3-dimethylimidazolium chloride or2-chloro-1,3-dimethylimidazolinium hexafluorophosphate.
 5. The methodfor synthesis of a halopyridyl-azacyclopentane derivative according toany of the claims 1-4, wherein the basic substance is a tertiary amine.6. A method for synthesis of an optically active allene-1,3-dicarboxylicacid ester derivative which comprises subjecting an acetonedicarboxylicacid and an optically active alcohol to esterification in the presenceof a basic substance and a dehydrating agent, or subjecting anacetonedicarboxylic acid ester (wherein the ester group is a lower alkylor phenyl group) and an optically active alcohol to transesterificationin the presence of a basic substance, to obtain an optically activeacetonedicarboxylic acid ester derivative, then subjecting the opticallyactive acetonedicarboxylic acid ester derivative to a reaction in thepresence of a basic substance and a dehydrating agent to obtain amixture of diastereomers of an allene-1,3-dicarboxylic acid esterderivative, and then subjecting the mixture of diastereomers to coolingand crystallization in the presence of a basic substance to obtain(R)-allene-1,3-dicarboxylic acid ester derivative or(S)-allene-1,3-dicarboxylic acid ester derivative.
 7. The method forsynthesis of an optically active allene-1,3-dicarboxylic acid esterderivative according to claim 6, wherein the optically active alcohol isa member selected from the group consisting of menthol, its derivatives,binaphthol and its derivatives.
 8. The method for synthesis of anoptically active allene-1,3-dicarboxylic acid ester derivative accordingto claim 6 or 7, wherein the dehydrating agent is2-chloro-1,3-dimethylimidazolium chloride or2-chloro-1,3-dimethylimidazolinium hexafluorophosphate.
 9. The methodfor synthesis of an optically active allene-1,3-dicarboxylic acid esterderivative according to any one of the claims 6-8, wherein the basicsubstance is a tertiary amine.
 10. A method for synthesis of a7-azabicyclo[2.2.1]heptan-2-one derivative which comprises subjecting anoptically active allene-1,3-dicarboxylic acid ester derivative and adienophile to Diels-Alder reaction to obtain a7-azabicyclo[2.2.1]heptene derivative represented by the formula (3), orits enantiomer of the formula (4), then selectively reducing theisolated olefin of the derivative obtained above, and subjecting theresulting product to ozone decomposition to obtain a ketoester compoundof a 7-azabicyclo[2.2.1]heptan-2-one derivative represented by theformula (5), or its enantiomer of the formula (6),

(wherein R¹ and R² are each a group derived from an optically activealcohol and R⁵ is a protective group for an amino group),

(wherein R¹ and R² are each a group derived from an optically activealcohol and R⁵ is a protective group for an amino group),

(wherein R² is a group derived from an optically active alcohol and R⁵is a protective group for an amino group),

(wherein R² a group derived from an optically active alcohol and R⁵ is aprotective group for an amino group).
 11. A method for synthesis of a7-azabicyclo-[2.2.1]heptan-2-one represented by the formula (7) whichcomprises further subjecting the ketoester derivative of7-azabicyclo[2.2.1]heptane represented by the formula (5) or itsenantiomer of the formula (6) according to claim 10 to hydrolysis anddecarbonation,

(wherein R⁵ is a protective group for an amino group).